Environmental exposures during critical periods of development can permanently reprogram normal physiological responses to increase susceptibility to disease later in life, a process termed developmental reprogramming. The Principal Investigator and Co-Principal Investigator of this U01 application are among the leaders identifying epigenetic targets for developmental reprogramming. However, studies in the field have focused on the target tissues for reprogramming events, and virtually nothing is known about whether similar and/or correlative epigenetic changes occur in surrogate tissues. This presents a Central Challenge for the field to move from experimental studies on target tissues and exposure-associated pathologies in murine models, to making connections between exposure-induced epigenetic changes in surrogate tissues and health outcomes in human populations. To address this Central Challenge, we have assembled an outstanding team of investigators, comprised of leaders in fields critical for success of the TaRGET II Consortium (T2C): Developmental reprogramming (Walker and Bartolomei), Epigenetics and Bioinformatics (Huang, Sun and Wang) and mouse models of genetic diversity (Threadgill). In Aim 1, we will generate reference epigenomic maps to identify epigenetic alterations induced in target and surrogate tissues by developmental reprogramming in response to specific environmental exposures, focusing on histone modifications and DNA methylation. Since surrogate tissue biomarkers may be accessed and/or interrogated at different times during an individual's lifetime, in Aim 2, we will track specific epigenetic alterations induced in target and surrogate tissues across the life course. In Aim 3 we will test the hypothesis that genetic heterogeneity modulates reprogramming events and/or the appearance and persistence of epigenetic alterations in target and surrogate tissues using genetically diverse mice from the Collaborative Cross. Together, these studies will identify those epigenetic marks that are the most robust against genetic background and most likely to be stable biomarkers of exposure and/or phenotypic consequence across the life course and genetically diverse populations.